Monday, January 31, 2011

The NHS is undergoing yet another reorganization. The split between purchaser and provider is being maintained, but rather than the purchaser being a medical manager led Primary Care Trust, in future Consortia of General Practitioners will determine which services are purchased and there will be more open competition among providers. The role of NICE will be diminished to merely offering advice.

There is a good deal of trepidation about the changes. Hospital doctors fear that GPs will not understand what secondary care providers might be offering; that they might go for a cheaper option without understanding why it is so cheap (ie it doesn't work); that they might repatriate services to GP practices inappropriately (eg near patient blood testing which is much more expensive than testing in laboratories with large machines and it is poorly quality controled, though superficially it does offer some attractive qualities like instant access, it is like comparing a Polaroid picture with a professional photographer).

I came across a good example of how things can go wrong. A Primary Care Trust decided to purchase GP blood tests from a different hospital from the one that patients were likely to be referred to for treatment. One result was that patients arrived for treatment with no blood test results on the hospital computer so that everything had to be repeated, but worse than this, the GPs would ring up the lab where the patient was registered to ask for advice on the recent blood test. Of course the hematologist had not seen the recent blood test an could not give an opinion. On the other hand, the haematologist at the hospital where the blood test was performed, could not help; he did not know the patient and in any case the contract was for blood tests, not their interpretation - that's why they were cheaper.

GP's are worried that they have no management training and may not be up to the job, but undoubtedly they will employ some of the displaced managers from the PCTs. Patients are worried that we will be back to post code prescribing. am worried that GPs will purchase complimentary medicine rather than cancer chemotherapy.

In the BMJ of January 29th, Des Spence, a left wing GP and regular columnist, voices his opinion on the changes. He admits that the previous government pushed up labor costs and reduced productivity, but he fears that the private sector will find this an easy way in to the NHS. The private sector, he says is not based on competition, but greed. He is scathing about the effect of competition in the USA. Healthcare costs are twice as expensive as in the UK and 50 million citizens have restricted access to care. Medicare and Medicaid together spend almost as great a proportion of a much larger GDP as the whole of the NHS does of the smaller British GDP, and when you add in the VA and CDC the proportion is greater. He also claims that the US system is more bureaucratic and that 'competition' has produced the world's most expensive drugs. He says that the US system is defined by overinvestigation, overdiagnosis and overtreatment. Mere activity is no measure of quality.

Saturday, January 29, 2011

Some people believe that every political decision should be decided by referendum. A good example why this is nonsense has just occurred in Switzerland. I quote from New Scientist:

SWITZERLAND has bowed to popular pressure and decreed that state-backed health insurance must pay for five types of “complementary medicine” between now and 2017, pending an investigation of their efficacy. In 2009, 67 per cent of the Swiss electorate voted, under the country's system of deciding issues by referendum, for five complementary therapies to be covered by health insurance. They are homeopathy, herbal and traditional Chinese treatments, neural therapy and anthroposophic medicine – which, among other techniques, uses mistletoe to treat cancer.

In December, however, the government's scientific panel advised that this would be illegal, as the law requires insurance to pay only for treatments that meet objective measures of efficacy, and these techniques do not. “The only solution was to pay for the five methods temporarily, but linked to an evidence-based evaluation,” says Ignazio Cassis, a member of the Swiss federal parliament and vice-chair of the Swiss Medical Association. “This isn't science, it's Swiss politics.”

The evaluation will be based on a report on existing studies of the techniques. This will be prepared by Swiss complementary practitioners and then reviewed by an independent body, possibly the UK's National Institute for Health and Clinical Excellence.

Friday, January 28, 2011

The point about RIC transplants is that they use the transplanted immune system to attack the host's leukemia. This graft-versus-leukemia (GVL) effect is difficult to separate from the graft-versus-host-disease (GVHD) that usually accompanies it. As we saw yesterday with the report of the German study chronic GVHD is very common and it can be very debilitating; so much so that I have had patients who have committed suicide rather than continue with it. I remember a teenager with ALL whose GVHD made him look like an old man of 80+. He drowned himself.

One way of attempting to prevent GVHD is to deplete the T cells from the graft, but this carries the risk of graft failure and relapse because some T cells are necessary for the graft to survive and in getting rid of the T cells you are apt to abolish GVL withe the GVHD. The German study seemed to have suffered from both problems, though the number of T-depleted transplants was small and the figures were not reliable.

In the October 21st issue of Blood Steve MacKinnon and his colleagues from teh Royal Free Hospital presented the results of a study in which he titrated the dose of alemtuzumab used to T-deplete. Most people use 100mg of alemtuzumab (5 days of 20mg/d infused into the recipient before the transplant) and this is the experience of MacKinnon and of the German group I wrote about yesterday. Previous British experience has been that the incidence of grade 2 to 4 acute GVHD has been 2% to 20% and with chronic GVHD has been 0% to 13%. The disadvantage of this approach has been slower immune reconstitution and therefore more frequent infections and possibly a lesser GVL effect.

In this study they have titrated down the dose of alemtuzumab. In four cohorts they used 60mg, 40mg, 30mg, or 20mg. 106 patients were transplanted - a mixture of AML, CLL, myeloma, NHL and Hodgkin's disease. There were 15 patients with CLL. All the donors were HLA matched siblings. The conditioning regimen was 5 days of fludarabine 30mg/sq m/d and one day of melphalan 140 ng/sq m. This is probably slightly more intense than the fludarabine/cyclophosphamide regimen used by the Germans.

There was a marked difference between those who received 20mg of alemtuzumab and those who received more than 20mg. The follwing differences were statistically significant. Grade 2-4 acute GVHD, 16% v 5%; extensive chronic GVHD 24% v 9%.

The two year progression-free survival was 60% and overall survival 73%. Full donor chimerism was 81% at 2 years. The non-relapse mortality was 15% at 2 years.

The use of alemtuzumab allows DLI to be used to eliminate mixed chimerism and therefore abort early relapse, without too great a risk of GVHD. Selected T cells may also be infused to protect against re-activated CMV infections and possibly other viral infections.

In future T-depleted transplants in the UK will be with 30mg rather than 100mg of alemtuzumab. It has to be recognized that this study was in a number of different diseases and teh CD52 positive tumors like CLL and NHL would adsorb more alemtuzumab than the myelod tumors, but even so 30mg seems to be enough.

Thursday, January 27, 2011

A long time ago I promised to review the German experience with reduced intensity conditioning allograft in CLL which was published in the October 7th 2010 issue of Blood.

They treated 113 patients from 16 centers. The patients were poor-risk, defined as refractory to or relapsed within 12 months of treatment with a fludarabine containing regimen, or relapse after autologous SCT or progressive disease in the presence of either del 11q or del 17p and/or unmutated IGHV genes or use of V3-21. Patients were aged between 18 and 65 with an ECOG score of 1 or better, normal organ function. Patients with Richter's syndrome were excluded. Related and unrelated donors were matched at 6 loci (more recently 10 loci are preferred).

Conditioning was Fludarabine 30mg/sq m for 5 days and cyclophosphamide 500mg/sq m for 5 days. With unrelated donors ATG 10 mg/kg/d was given for 4 days. The donor source was peripheral blood harvests generated by G-CSF stimulation. For a limited period (June 2002 to November 2005 an alternative conditioning regimen was used, FC + 2Gy TBI on day -9 and alemtuzumab 20mg/d for 5 days. After November 2005 an intensified conditioning regimen was introduced for refractory patients consisting of fludarabine 30 mg/sq m.d for 5 days, busulfan 4mg/kg/d for 3 days, cyclophosphamide 30 mg/kg/d for 2 days. GVHD prophylaxis was with cyclosporin A. Some patients received short courses of methotrexate or mycophenolat mofetil. DLI was admoinistered no earlier than 4 weeks after complete withdrawal of cyclosporin A in case of incomplete donor chimerism or MRD.

13 patients had to be excluded from analysis because of ineligibility. 10 patients did not receive a transplant (1 progressive disease, 3 Richter's transformation, 2 refusal, 4 no donor found).

Of the remaining 90, 24 had uncontrolled refractory disease at time of SCT. Of the 90, del 17p was found in 13, and del 11q in 26. 40% had sibling donors the rest volunteer donors. 65 patients had FC conditioning, 12 FCB and 12 the alemtuzumab-containing regimen.

Neutrophil and platelet recovery occurred in 85/86 with data available and complete donor chimerism was achieved in 66/80 and incomplete chimerism in a further 6. 7 failed to engraft and one had graft failure after partial chimerism - these failures only occurred with the FC and Alemtuzumab regimens. 6/7 had some degree of mismatch and 2 had marrow rather than peripheral blood grafts. 7/8 had autologous recovery and one was salvaged with a 2nd transplant. No patient died of the conditioning which caused a median time in hospital of 22 days (range 0-150 days). There were 2 unrelated deaths in the first 3 months.

Clinically significant GVHD occurred in 45% either after primary transplant or after DLI but grade 3 or 4 GVHD was seen in only 14%. Chronic and extensive GVHD was 73% at 2 years. 65% of those who were alive at 1 year were still on systemic immunosuppression.

33 of the 90 patients died; 16 of progressive disease, 4 of acute GVHD, 5 of chronic GVHD, 5 of infection, 1 of transplantation-associated microangiopathy and 2 of unknown causes. Non-relapse mortality at 4 years was 23% and overall survival at 4 years was 65%. Of the 10 patients who did not get a transplant 7 had died (5 from progressive CLL and 2 from off-protocol allograft)

A CR after allograft was achieved in 73% though 11% of these were already in CR at the time of allograft. A further 21% achieved a PR. At 4 years the relapse rate was 40%. Taking account of the 17 relapse-free mortality cases, the single secondary malignancy and the 8 non-engraftments, the event free survival at 4 years was 42%.

There were some MRD measurements in some of the patients. In those who had data available 39/52 were event-free at 1 year and 27/52 were MRD negative. There were 2 relapses and one non-relapse death among the 27 who were MRD negative at 12 months. 2 others became MRD +ve on follow up. Patients who had a clear GVL effect had the worst GVHD effect. 15 patients required DLI and 5 became MRD negative following this.

So what factors can predict a good or poor outcome? First of all, this study confirms that allografting is an effective treatment for del 17p patients. But having uncontrolled disease at the time of transplant definitely affected outcome adversely. This suggests that once teh criteria for allograft are met it is foolhardy to delay until the disease bulk increases so that no other hope is left. Some patients elect to do just that. Better to grasp your courage and take the chance.

Because matching was only available at 6 rather than 10 loci, many of the grafts would today be considered partially mismatched. This gave the opportunity to assess whether this made a difference. It didn't. This ought to encourage patients to go ahead with an allograft even though a fully matched donor is not available.

There was a high rate of chronic GVHD. One way of avoiding this is to T-deplete the graft. The attempt to do this with alemtuzumab in this study was unsuccessful with shorter event-free and overall survivals. However the authors feel the small numbers involved and the non-randomized allocation of patients to receive T-cell depletion, by no means rule alemtuzumab out of court. I shall have more to say about this later.

In summary, this is the most complete study of RIC transplants in CLL yet published. 60% of patients will be still alive at 4 years and it is the most effective way of treating TP53 deficient disease. However this 60% are not all cured and chronic GVHD is still a major hazard. Finally, if you are taking this option, don't leave it too late.

As readers know I am less than enthusiastic about ZAP-70 as a surrogate for IGHV mutations. I came across this conversation on the web which I find interesting.

John C. Byrd, MD: There is a lot of hype about other biomarkers that were being used as surrogates because IgVH gene mutation status was initially harder to obtain. However, that has changed, and now many good commercial and clinical labs at CLL centers are able to obtain these findings. Other tests, like the 70-kDa zeta-associated protein (ZAP-70), I find very challenging to use in my CLL practice. Patients will bring results from 3 different tests that have 3 different answers. The ZAP-70 is clearly a valuable test in the research setting, but for the purposes of translation into real practice, it has not been easily reproducible across different laboratories.

Jennifer R. Brown, MD, PhD: I have that exact problem. Frequently, ZAP-70 may be the only prognostic test patients come in with. They have not had cytogenetic analysis by FISH, nor do they know the mutational status of IgVH. They may have put a lot of stock in their ZAP-70 result even though, as you note, it may not be interpretable.

Wednesday, January 26, 2011

I have already written about PARP inhibitors here so this will be a follow up for some. A paper in the November 25th Blood tells of the pre-clinical basis of these new agents which are now in a clinical trial. The paper is from Tanya Stankovic from Birmingham and is a collaboration between several labs including my old lab. The PARP inhibitor olaparib induces significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivoVictoria J. Weston, Ceri E. Oldreive, Anna Skowronska, David G. Oscier, Guy Pratt, Martin J. S. Dyer, Graeme Smith, Judy E. Powell, Zbigniew Rudzki, Pamela Kearns, Paul A. H. Moss, A. Malcolm R. Taylor, and Tatjana Stankovic. Blood. 2010; 116(22):4578-87.

This is of interest to those who are 11q23 deleted. The Ataxia Telangiectasia Mutated (ATM) gene is frequently inactivated by either deletion or mutation in lymphoid malignancies such as CLL, T-PLL, and mantle cell lymphoma (MCL) and is associated with defective apoptosis in response to alkylating agents and purine analogues.

They suggested that olaparib would be an appropriate agent for treating refractory ATM mutant lymphoid tumors.

Olaparib, here, targets only proliferating cells with ATM dysfunction, consistent with a cytotoxic mechanism involving the conversion of single-stranded DNA breaks into double stranded breaks during DNA replication that cannot be repaired efficiently in cells with a homologous repair (HR) defect. PARP inhibition did not lead to the same degree of cytotoxicity of ATM deficient tumor cells as BRCA mutant cells because the major role of ATM is in sensing the damage that is subsequently repaired by HR repair in which Rad51, BRCA2 and BRCA1 proteins play a major role. The response of ATM mutant lymphoid tumor cells to PARP inhibition is, therefore, comparable to, although not the same as, the scenario previously described for BRCA1/2 mutant breast carcinoma cells which has resulted in Phase I and ongoing Phase II clinical trials with orally administrated olaparib, providing evidence that this agent is well tolerated and exhibits clinical potency. Thus, the clear differential sensitivity of ATM mutant lymphoid cells to submicromolar concentrations of olaparib and the necessity to improve treatment for chemoresistant ATM mutant lymphoid tumors makes olaparib a compelling candidate for trials in these malignancies. Indeed, progressive tumors with especially active proliferation centers may provide the idealcellular scenario for targeting by olaparib with the aim of at least delaying disease progression.

It is possible that loss of a single ATM allele by 11q deletion does not affect ATM function and it is therefore conceivable that only 11q-deleted tumors that exhibit mutation in the remaining ATM allele and consequently lose ATM function willrespond differentially to treatment with olaparib. While olaparib monotherapy is an attractive proposition for treating these tumors, there is also the possibility of combining olaparib with chemotherapy agents.

Clinical trials of olaparib in CLL, T-PLL and MCL have begun in the UK.

The incidence of CLL in Taiwan is increasing. The incidence of CLL has always been recognized as 10 times as great among Caucasians compared to that of East Asians. However, a paper in Blood The incidence of chronic lymphocytic leukemia in Taiwan, 1986-2005: a distinct increasing trend with birth-cohort effectShang-Ju Wu, Shang-Yi Huang, Chien-Ting Lin, Yu-Jr Lin, Chee-Jen Chang and Hwei-Fang Tien Blood. 2010;116:4430-4435reports a drastically increasing trend. The epidemiologic data of CLL for Taiwanese and Caucasian Americans during 1986 to 2005 were obtained from the Taiwan SEER database. The age-adjusted incidence rate of CLL for Taiwanese was continuously increasing during the 20-year period while that for Caucasian Americans remainedsteady. A much stronger birth cohort effect was identified for Taiwanese but not for Caucasian Americans. This effect corresponded to the westernization of lifestyle in Taiwan since 1960. They concluded that, in addition to the ethnic difference of incidence, there is distinct increasing incidence trend of CLL in Taiwan. The strong birth-cohort effect underlying this increasing trend indicates that lifestyles and environmental factors may play a role in the development of CLL for Taiwanese.

It has long been known that CLL cells need help to be able to survive. Several studies have shown that it is what goes on in the tissues rather than the blood that provides the drive for CLL cells to multiply and resist apoptosis. A number of different cells have been implicated including 'nurse' cells described by Tom Kipps group and T cells according to Sylbia Deaglio's group in Italy.

I have been going back through old copies of Blood before disposing of them and I came across this article in the issue from November 18th last year. Soluble CD14 is a novel monocyte-derived survival factor for chronic lymphocytic leukemia cells, which is induced by CLL cells in vitro and present at abnormally high levels in vivo by Martina Seiffert, Angela Schulz, Sibylle Ohl, Hartmut Dohner, Stephan Stilgenbauer, and Peter Lichter. Ulm, Germany

The bottom line is that monocytes help in the survival of CLL cells by secreting soluble CD14, which induces nuclear factor kappa B activation in these cells, and that CLL cells actively shape their microenvironment by inducing CD14 secretion in accessory monocytes.

CD14 is a cell-surface receptor present on monocytes and macrophages, and to a lesser extent on neutrophils and dendritic cells. By binding bacterial Lipopolysaccharide (LPS), CD14 helps in the activation of Toll-like receptor (TLR)-4 signaling, which subsequently results in the activity of NF kappa B, AP1, and IRF3 transcription factors. Although LPS is considered its main ligand, CD14 also recognizes other pathogen associated molecules. A soluble form of CD14 is present in body fluids, like blood, saliva or breast milk, where it is involved in innate immunity by conferring its signaling activity to cells that do not express CD14. By adding recombinant soluble CD14 to CLL cells in culture, they observed increased CLL cell viability. Consistent with this they found that stimulation of CLL cells with soluble CD14 resulted in an augmented activity of the NF Kappa B components, p50 and p65, which are known to be constitutively active in primary CLL cells and are associated with their survival.

It is known that soluble CD14 is raised in patients with CLL and that it parallels the B-cell count.

I am enjoying the course on moral philosophy being broadcast by the BBC and led by Michael Sandel.

Yesterday he contrasted the utilitarianism of Jeremy Bentham with the categorical imperative of Immanuel Kant.

Bentham believed in the greatest happiness for the greatest number. In many ways many of us would go along with that until it comes to the hard questions.

One example: a trolley bus is careering down a hill out of control. The brakes have failed and five workers on the tracks below are bound to be killed. But there is a siding to the right with only one worker on it. The driver can still steer. Should he steer to the right and kill one to save the five? Most people take this choice, but when the same question is put in a way that involves a direct act of murder most would hold back.

There are 5 patients waiting for a transplant. Two need kidneys, one a liver, one a heart/lung and the fifth a pancreas. There are no donors and they are all going to die. But in the next room a fit young man with the right blood group has come in for a check-up. He is taking an afternoon nap. The surgeon has a bright idea, "I could nip in and take the required organs from him. True I would lose one life, but I would save five."

There would be no support for this action - even from the relatives of the potential recipients.

Kant saw the flaws in utilitarianism and propounded his own ideas. Human dignity trumps mere numbers. He talked about categorical imperatives, principles that are intrinsically valid, good in and of themselves. One of these imperatives is the idea of human rights or human dignity.

But it is easy to put hard cases to the committed Kantian. For example torture would be absolutely forbidden according to Kant. But supposing there is a bomb on a plane which will explode and kill 500 people. The man who put the bomb on the plane has been caught but refuses to tell where it is. Does anybody believe it would be wrong to waterboard the bomber to save the lives of the 500? Kantians do. Politicians avoid the question by calling the idea hypothetical, saying that such situations don't occur in real life. But they do.

A recent German case illustrates the dilemma. A young child was kidnapped. The kidnapper was caught and the ransom retrieved, but he refused to say where the child was. The police chief threatened him with torture and he caved in and gave the location of the child. He admitted that he had killed the child shortly after the kidnapping. He was prosecuted for murder and received a life sentence. But, and here's the rub, the police chief was prosecuted for violating the kidnapper's human rights. You or I might think that the murderer had forfeited his human rights in this case, but under the German Constitution, the rights of all its citizens are sacrosanct.

I believe that after the Third Reich so violated the human rights of 6 million Jews, the German conscience so pricked that they felt it necessary to incorporate this principle of their favorite philosopher in law. So many European countries were complicit in the persecution of Jewry that they raised no objection to this guiding principle throughout Europe and the last Labour government in the UK incorporated the European Convention on Human Rights into UK law.

In the UK we have managed without a written constitution for thousands of years and the German experience shows the wisdom of that. The sorts of dilemmas that Sandel has highlighted demonstrate the futility of laying down absolute principles. In the 2000+ years since Socrates the greatest minds have disagreed about these questions of moral philosophy - how are we supposed to resolve them? Each case must be judged on its merits. Sometime the law is an ass and a wise judge will recognize that.

One of Kant's categorical imperatives concerns lying which he says is always wrong. So you have a RAF pilot hidden in your hayloft. The Gestapo calls and asks you if you have seen one and Kant would say you have to betray the pilot because it is wrong to lie. I would say that the Gestapo officer has forfeited his right to be told the truth.

The same applies to imprisoned murderers who have been denied the right to vote in general elections. By their actions they have forfeited some of their human rights. Not according to the European Court which holds the UK is in contempt for its policy.

Tuesday, January 25, 2011

I watched a debate on BBC4 last night about Fairness and the Big Society. It was conducted at the Royal Institution and moderated by Michael Sandel, the Harvard Professor.

The audience, being a BBC audience, was packed with left-wing students, which rather threw Sandel when they voted en masse against a communitarian solution to fairness - in reality they were voting against anything associated with the Tories.

However, some interesting points. A large number of people felt that fairness equated with equality. Well, it may do, but life is unfair. We are not all born equal, except in the sight of God. We are all born with natural talents. However hard I try I will never make a good carpenter or be able to play football for anything better than a pub team.

The question was posed as to whether it was fair that Wayne Rooney should make £11.2 million a year for playing football while a care worker has to make do on £12,000 a year. The point was made that there is a market out there for footballers and players are paid what the market will bear. It's all a question of supply and demand. Very few people can do what Wayne Rooney can do and people are willing to pay and watch it. On the other hand hundreds of thousands can do a care workers job and if she doesn't like her job there is no shortage of people willing to fill her shoes.

Equality of opportunity is one thing that most agree on and interestingly an overwhelming majority of the audience felt that they were either doing better than their parents or expected to do so. Despite this the UK is supposed to have less social mobility than most other OECD countries even including the USA. Denmark is held up as the paragon of social mobility (though the standard rate of income tax there is 52%). Certainly class and the public school system have in the past been a barrier to social mobility, but there is a problem in abolishing privilege: social mobility involves some moving down as well as some moving up. People tend to be reluctant to let their children suffer. It is noticeable that among left-wing politicians, just as much as among those on the right that nepotism abounds. Most successful actors are left-wing. Take the Redgraves. They have been called Trotskyites, yet if you are a Redgrave family member you find it easy to be a thespian. Inherited talent or nepotism? When you see Harley street doctors making it easy for their sons to follow them in the profession, ask the same question.

There is a hint of left-wing envy and snobbery about the whole debate. We live in an unfair world, because we are not all born equal and unequal things happen to us. To suggest that everybody ought to go to university just because that is what the rich do is nonsense. They have even dumbed down university courses to make it possible. An academic education is appropriate for academics but not for carpenters. I am all for everybody being educated to the limits of their ability, but to pretend that that means living away from home for three years, attending lectures and reading books is plain silly. For most, an apprenticeship is more appropriate. That is nothing to look down on. My most revered scientist, Edward Jenner, was apprenticed to a barber surgeon from the age of 13.

I respect my gardener because he grows beautiful camellias for me, my window cleaner because he reaches the parts that I cannot, my odd-job man because he replaced my damaged locks, the girl on the supermarket check-out because she had a cheerful word and was patient with me while I packed my bags, my patients because they make me feel useful and the homeless men who come to our church for food and clothing because they are human beings made in the image of God.

"From each according to his ability; to each according to his needs" is a slogan of Karl Marx, which is all very well in theory but in real life, it cannot be enforced by compulsion and no-one adopts it voluntarily. St Paul wrote "He who will not work, neither shall he eat." But even societies that start out with such an ideal find themselves soft-hearted when it comes to denying a beggar despite warnings that the money will go to drug dealers.

Perhaps we have to accept that life is unfair and read every situation as it comes along in a pragmatic way. I can't imagine what I would do with £11.2 million a year but I would certainly find it difficult to manage on £12,000. Income tax at 52% would make me think of emigrating, no matter how good the health service.

There is a famous science fiction story which envisioned a society where everyone was made to be equal. The bright had to wear headphones that played weird noises in their ears to stop them concentrating. The strong had to wear 40 pound bags on their backs to handicap them. It was an equal society but unfair to the talented.

I should like to see a society where everyone was enabled to fulfill their talents in meaningful work and where people were valued as people. No-one can help being born blind or deaf and they shouldn't be disrespected because of it. They should be helped to make the most of what they have. Wayne Rooney was born with a certain agility and dexterousness. No doubt he is such a good footballer because he has applied himself to training and practice, though even with that application I could never play professional football. Nevertheless, much as I approve of his ability to capitalize on his talent I believe he has a responsibility to the society that has nurtured him. Sportsmen have a great rewards and opportunities; they should use their good fortune for the common good. It used to be called Noblesse Oblige.

Monday, January 24, 2011

As you will see, I have just posted a blog I started last Wednesday. I have an unpleasant few days since last Wednesday, with pain and fatigue making it difficult for me to do anything other that lie there and stare at the wall. With more than a 5 week gap between treatments, I had forgotten what an unpleasant thing chemotherapy is.

Today I am feeling a whole lot better and am able to sit at my desk, though I still haven't started on setting up my train set.

My discomfort has coincided with a poor showing by England in the one-day cricket internationals. I have refrained from crowing over the test matches in which the Australians got a drubbing since I know that these things go-around and then come-around. Liverpool FC have replaced their manager with Kenny Dalglish, the Return of the King, they are calling it. He had a decent win on Saturday. New managers can make a huge psychological difference, but success in football matches depends on fine margins. Manchester United and Arsenal continue on their successful ways and Spurs continue in the top 5. Chelsea seem to be in trouble and must beat Bolton tonight if they are not to have lost hope. Manchester City remain a group of expensively purchased stars, but not yet a team.

We have had a spell of dry weather and some sunshine, but temperatures have remained just above freezing by day and just below at night.

Family have visited a bit, but viral infections have limited this. I am still struggling with a new 1000 piece jigsaw puzzle and with NT Wright's "Virtue Reborn". January is nearly over.

Wednesday, January 19, 2011

"There ought to be a law against that!" says David. "I'm sorry but there isn't one." replies Richard. "Then let's make one!" exclaims David."Well, we could, I suppose," explains Richard, "but we wouldn't be able to catch this lot because laws don't operate retrospectively."

This is what Paul is explaining. The Law can have nothing to do with Abraham because Abraham lived hundreds of years before Moses was given the Law. God made a promise to Abraham even before he left Haran and it is through this promise we are saved. "All people on earth will be blessed through you." Genesis 12:3. This covenant promise was made by God in an unconditional way. It did not depend on the behavior of Abraham or any of his descendants.

Paul takes an example from everyday life (Galatians 3:15). The example is a last will or testament. Once it is signed, sealed and delivered after a person's death, it cannot be altered. So long as the testamentor was of sound mind and the will was properly witnessed, the cats' home is going to benefit and not the long-lost cousin in Australia. God made a covenant with Abraham and God will deliver.

But this passage in Galatians has two major problems. The first is how Paul goes on about singular and plural 'seeds'. In English this doesn't make much sense to us, since 'seed' is a collective noun; it can mean one seed or many. The same is true for both Hebrew or Greek, the languages that Paul might have been referring to.

The second is the 430 years since the promise was given. On some accounts this seems to be an underestimate; some interpreters put the period as 645 years. I don't want to go into a great deal of detail about this; it seems to me to fall into Paul's category of arguing about meaningless genealogies, but I suspect that the answer to both questions lies in the fact that the promises were repeated in Genesis 22:18 to Abraham, in 26:4 to Isaac and 28:14 to Jacob. And with each repetition there is a choice between plural seeds and singular seed. It was to Isaac not Ishmael that the promise was given, and to Jacob not Esau and as a matter of fact to Judah and not the 11 other sons. Not to Levi, through whom the priesthood and Mosaic law derived; not even through Benjamin, from whom we have the writer of most of the New Testament and the greatest preacher ever. It is through Judah, that seed, that we have the Christ, the fulfillment of all prophesy and promises.

If the inheritance depends on the law; it no longer depends on a promise. What sort of a promise is it that it takes the law to enforce it? God in his grace gave the inheritance to Abraham through a promise. Our salvation depends on a promise.

As a father, I have often fallen down on my promises. Life encroaches and one forgets. But this was a promise from God. The all-seeing, all-powerful God. He does not renege; he does not forget. Our salvation is all of grace; none of works. We bring nothing to the party except our sins - and these to be washed away.

Monday, January 17, 2011

Emili Montserrat's group in Barcelona has just published its experience with autoimmune phenomena in CLL over the past 28 years Blood 2010, 116:4771-6. Among 961 patients with CLL seen in that time, autoimmune cytopenias were confirmed in 70 ((7%). 49 had AIHA, 20 ITP and one had both at presentation though a further three with ITP later developed AIHA. In 3 patients the autoimmune thrombocytopenia preceded the diagnosis of CLL and in a further 19 the diagnosis was simultaneous. In 35 (50%) the autoimmunity occured during or soon (immediately up to 10 months) after therapy (8/204 after fludarabine, 12/231 after chlorambucil).

Autoimmunity was associated with advanced clinical stage, high lymphocyte count and short lymphocyte doubling time. Among more modern prognostic factors, beta-2 M, CD38and ZAP-70 were associated with autoimmunity but too few patients had IGHV mutations or cytogenetics done to make a correlation with these. There were no significant differences between overall survivals of those with and without autoimmune phenomena.

Neither Binet nor Rai staging takes account of the effect of autoimmunity. Thus patients with ITP are automatically assigned to Rai stage 4 or Binet stage C. I have always though this nonsensical and Montserrat agrees with me. He differentiates between Binet stage C (immune) and C (infiltrative). They compared 19 patients with stage C (immune) with 54 patients with stage C (infiltrative) The groups were demographically similar except that the infiltrative group had higher beta-2M levels and more marrow infiltration. There was a major difference in survival between the two groups with the immune patients having an average survival of 7.4 years and the infiltrative patients having an average survival of 3.7 years.

The reason for this difference was the relative response to steroids with immune patients being downstaged to stage A in 84% of cases and the infiltrative patients being downstaged to stage A in only 16% of cases. The ITP cases did slightly better than the AIHA with 100% downstaged compared to 75%. The development of an autoimmune disease during the course of the CLL did not significantly affect prognosis, though for patients with early stage A average survival was 9 years compared to that of stage A patients who did not develop autoimmune phenomena who survived on average for 10 years. Median survival for stage A were 10.2 years, for stage B 5.6 years, stage C immune 7.4 years and stage C infiltrative 3.7 years.

Agreeing with what was found in LRFCLL4 the prevalence of AIHA after chlorambucil and after fludarabine was similar at 5% and 4% respectively.

The same group have also published a systematic review of the subject in Haematologica and I quote extensively from it.

Among the additional points they make are that the monoclonal B cell lymphocytosis (MBL) is markedly more common in patients with supposed idiopathic AIHA or ITP than in matched controls which emphasizes the importance of excluding CLL and other chronic lymphoproliferative diseases in patients with AIHA and ITP.

In the early 1990s we published our concern that treatment with purine analogs (particularly fludarabine) was associated with a higher frequency of autoimmune cytopenia (Myint H et al, Br J Haematol 1995;91:341-4) and several other authors agreed. This was thought to be related to prolonged suppression of CD4+CD25+FOXP3+ regulatory T cells (Tregs) which has been shown to lead to autoimmune disease, and Tregs are highly sensitive to fludarabine. The cases reported were mainly in patients who had been heavily pre-treated with purine analogs. As a result of these observations, there has been agreement that purine analogs should be avoided inpatients with a history of autoimmune cytopenia, particularly if related to purine-analog therapy.

More recent trials in patients treated with first line therapy have suggested that the risk for developing autoimmune cytopenia after purine analog exposure is not greater than with other agents though cases may be more severe. In the UK LRFCLL4 trial no differences were observed in the percentage of patients becoming DAT positive after therapy (14% chlorambucil, 13% fludarabine, and 10% fludarabine plus cyclophosphamide), but the incidence of AIHA was significantly lower in patients treated with fludarabine plus cyclophosphamide (5%) than in those allocated to receive chlorambucil (12%) or fludarabine alone (11%) (p<0.01). This suggests that the addition of cyclophosphamide to fludarabine might have a “protective” effect on the appearance of AIHA. An earlier smaller study from MDACC supports this low incidence of AIHA in patients treated with fludarabine, cyclophosphamide and rituximab. The most recent data come from the German CLL 8 trial of patients with CLL requiring treatment and without clinically apparent autoimmune cytopenia. When treated with fludarabine and cyclophosphamide with or without rituximab, the rate of AIHA was <1%. Taken together these results demonstrate that the risk of AIHA is not higher following regimes in which fludarabine and cyclophosphamide (with or without rituximab) are given together in comparison to the risk seen after older therapies for CLL.

Treatment of patients with CLL and autoimmune cytopenia is largely based onexpert opinion and depends on whether the patient’s CLL requires treatment at the same time. In those patients with immune cytopenia in the context of quiescent CLL, the treatment is the same as idiopathic AIHA initially with corticosteroids, and then in patients who fail to respond or relapse quickly, alternative immunosuppression such as ciclosporine, mycophenylate or azathioprine, or sometimes splenectomy. There are case reports of the use of combinations of rituximab with or without immunosuppression with good effect; alemtuzumab has also been successfully used. Intravenous immunoglobulin can be useful where a rapid response is needed though as a single agent it will not give lasting effects. The new thrombopoietin receptor agonists may be effective in CLL associated ITP as they are in primary ITP. Despite the fact that the problem is destruction rather tha failure to produce blood elements, supportive care should include blood product transfusion as clinically indicated. Folic acid in AIHA and local efforts to control bleeding in ITP may also be required. Failure of autoimmune cytopenia to respond to conventional treatment is considered an indication for anti-CLL therapy.

Given the concerns about therapy-triggered AIHA, there has been recent interest in the most appropriate treatment for patients with active CLL and immune cytopenia or a positive DAT Monotherapy with fludarabine is not appropriate, either in terms of risk of AIHA or efficacy in treatment of CLL. The studiesquoted in this article suggest that treatment with FC with or without rituximab does not provoke an excess of AIHA sompared to previous treatments, and that patients with a previous history of AIHA or a positive DAT might be safely treated with such regimens. Indeed, optimal treatment of CLL may be the most efficient way to treat associated cytopenias. However, patients with active AIHA or ITP are still excluded from clinical trials, and given ongoing concerns about using fludarabine inthis situation, alternative regimens which do not feature fludarabine such as R-CVP and R-CD have also been explored.

ITP in CLL is difficult to diagnose and its incidence may be underestimated. There is no specific test and thrombocytopenia in CLL is more commonly due to splenomegaly and bone marrow failure secondary to infiltration by disease. Thrombocytopenia in a patient with CLL can be considered immune mediated when there is a sudden profound fall in platelets (>50% fall to a platelet count <100 x 109/L) in the absence of splenomegaly, infection or chemotherapy and with plentiful megakaryocytes in the bone marrow. In advanced disease, anemia usually occurs before thrombocytopenia, so isolated thrombocytopenia is more likely to be immune in origin. However, ITP with a gradual rather than sudden decline in platelet count is seen more commonly in adults than classic acute ITP of childhood, and can provide particular diagnostic difficulties. Response of thrombocytopenia to steroids may be the diagnostic test.

Sunday, January 16, 2011

ASH 2010 abstract 43 summarizes a collaboration between 16 different laboratories in which a total of 7596 patients with CLL who had had their V genes sequenced were compared, looking for evidence of stereotypy. They have assembled three times as many cases as ever published before (around a thousand of them came from my old lab). Stereotypy was found in 2308 (30.4%) cases. 218 sequences were placed in the V3-21 cluster, the first one to be recognized and the most common. The second most common with 184 sequences, was different in that it was not confined to a single V gene type. This is typical of an immune response; what is important is that the antibody combining site or B cell receptor (BCR) is configured to combine with an antigen.. This cluster utilizes different IGHV genes of Clan I (ie IGHV1-2, 1-3, 1-8, 1-18, 5-a, 7-4-1) but the same three amino acids (glutamine-tryptophan-leucine) at a vital point of the CDR3 (positions 108-110) which constitutes the BCR.

As more sequences have been studied, more stereotypes have been recognized. In some cases there are only two members of a cluster – but then there should be no cases with identical sequences for the antibody combining site unless something bizarre was going on, so even two with the same sequence is suspicious.

The question then has to be asked whether if enough cases were sequenced, would every CLL belong to one cluster of stereotypes or another. To that, the answer is no. As more cases are sequenced the rate of increase in stereotypes found diminishes and the authors think it won’t exceed more than 1 in 3 cases. Do stereotyped and non-stereotyped cases differ qualitatively? Probably not. Most stereotyped cases are unmutated and it will probably possible to recognize patterns of behaviour for these and even to devise targeted treatments. Most of the mutated subtypes are not stereotyped and most will not require targeted treatment.

Friday, January 14, 2011

Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer of elderly and immunosuppressed patients that is caused by the Merkel cell polyoma virus. Patients with MCC are 30 times more likely than the general population of developing CLL. A paper in Blood (2010; 116:5280-4) from Cologne reports on the clonal integration and truncating mutations of the large T antigen of Merkel cell polyoma virus in CLL patients. Normally this is only found in patients with MCC, but the German group found copies of the virus in 19/70 highly purified tumor cells from CLL patients. There were 3-4 logs fewer copy numbers compared to MCC tumors. In 6/19 cases there were mutations of the viral helicase gene, which indicates that this was not just a passenger virus.

One possible explanation for these findings is that the high incidence of MCC in CLL is not simply due to immunodeficiency, but that the MC polyoma virus is oncogenic (cancer causing) in B lymphocytes.

"Older, powerful men boosted their social status by keeping boys as sexual playthings and the practice was celebrated in song and dance, a military study claimed."

"American social scientists employed to help troops understand the local culture reported that homosexual sex was widespread among the Pashtun ethnic group in southern Afghanistan."

"The study, called 'Pashtun Sexuality', said that as well as willing sex between young men, "boys are appreciated for physical beauty and apprenticed to older men for their sexual initiation".

"Strict separation of men and women, coupled with poverty and the significant expense of getting married, contributed to young men turning to each other for sexual companionship.

"To dismiss the existence of this dynamic out of desire to avoid western discomfort is to risk failing to comprehend an essential social force underlying Pashtun culture," the report said.

"The practice of 'bache bazi' or boy play, is known throughout Afghanistan, but is particularly renowned in the city of Kandahar next to Helmand, where prepubescent boys are widely admired."

"Western soldiers often report feeling unease at the attentions of their Afghan comrades, who are affectionate with each other and sometimes wear make-up."

"British troops have also talked of their disgust at police or militias keeping young boys as hangers on."

"A spokesman for the Ministry of Defence said: “Afghanistan is a sovereign nation with its own law under which the sexual abuse of children is illegal." I am reminded of two instances where a rather different attitude was taken by those in authority.

The first was the British attitude to the practice of Sati in India. Led by William Wilberforce and William Carey the Hindu practice of burning a widow on her husband's funeral pyre was abolished. When the Indians protested that it was their tradition the British Governor is supposed to have replied, "Yes, well, we have a tradition in England that when people burn widows we put a rope around their necks and hang them from the nearest tree. If you want to continue with your tradition, we shall continue with ours."

The second was the attitude of the Angels on whom a sexual assault was attempted in Sodom. I didn't notice God saying that he must respect their culture and anyway the small boys enjoyed it.

It NATO forces are in Afghanistan to support this culture then the sooner they come home the better.

Thursday, January 13, 2011

Although some are obsessed with finding surrogates, I still support the test for IGHV mutations as one of the best prognostic markers for CLL. CD38, ZAP-70 and CD 49d all have their advocates, but each has its drawbacks and the only thing in favor of them is that most labs now have a flow cytometer. However, a gene sequencer is no more expensive to buy and the sequencing of IGHV genes has became a largely automated test. I saw a paper the other day which had collected gene sequences from over 8000 CLL patients.

There have been developments in IGHV testing that have made it a much more interesting tool. They can be summed up by the word 'stereotypy'.

When I first stared talking to Nick Chiorazzi about IGHV genes he told me about five sequences he had determined from patients who originated from all over the world. They had all used the same IGHV gene, V4-39, and they all had surface IgG rather than IgM+D. Furthermore they all had the same Ig sequence. Since there are a possible thousand billion different sequences, it was difficult to believe that there hadn't been some cross contamination. But Nick assured me that they had checked for this and the identity was confirmed.

Then Gerrard Tobin and Richard Rosenquist produced the astonishing finding that patients whose CLL used the V3-21 gene had a poor prognosis whether they were mutated or unmutated. When I saw the sequences it became clear that many of the V3-21 had identical or near-identical sequences. It all suggested that at least for some CLLs the leukemia had originated in a clone of B lymphocytes that was expanding in response to stimulation by a single antigen.

The question then was, if there are these two families of cases with identical sequences, are there others? Enter Kostas Stamatopoulos from Greece. In collaboration with workers in many countries he has established that approximately one patient in three has a IGHV sequence that belongs to a stereotyped family. Moreover for some of these there is a clinical correlation - all members of the family behave similarly, and the originating antigen has been determined. For some of the families the members are too few for us to be accurate about how they will behave, which provides a justification for everybody to have their V genes sequenced. Sequences that were near-identical for a number of patients were given the name 'stereotypes'.

Wednesday, January 12, 2011

Today I had my Hickman line replaced on the other side. I had had Augmentin for 5 days since the other one came out. Augmentin is not pleasant causing colic and diarrhea, but having had the line removed and the abdominal symptoms subsided I am feeling a lot better with much more energy. I think the next chemotherapy will be next Monday.

I have managed to complete a 1000 piece jigsaw with my wife - one piece missing! and I have started a book by Tom Wright, the Bishop of Durham, Virtue Reborn.

In the meantime I have read a John LeCarre from a few years back. Our Game is about two spies who were retired when the Soviet Union fell, but they can't leave well alone and get involved with a rebel movement in the Caucasus. LeCarre seems to be supporting the Blairite interventionist line (Afghanistan, Bosnia, Kosovo, Iraq, Sierra Leone) but it seems to me that it is impossible to tell which of the combatants has right on their side. As usual the story is about betrayal and involves betraying a friend, a lover, and a country.

We seem to be watching a lot of Sherlock Holmes recently. I watched the recent movie starring Robert Downey Jr and an old one Without a Clue with Michael Caine and Ben Kingsley. Then we started on the old Basil Rathbone series which has been digitally remastered. I still think that the Jeremy Brett TV series was the best.

Tuesday, January 11, 2011

1066 is the date that most people take as the beginning of the English nation but I'm not sure why. It was merely the date when the French Vikings beat the English Vikings in what was effectively an internecine battle for the crown. There was an largely English province of the Roman Empire - Britannia - and it was from here that the first Christian Emperor, Constantine, came. When the Romans left in about 410 AD there were invasions by Angles, Jutes, Frisians and Saxons, though Roman influence persisted to some degree for another 200 years.

Anglo-Saxon England until the 9th century was dominated by the seven kingdoms of Northumbria, Mercia, East Anglia, Essex, Kent, Sussex and Wessex. Alfred the Great of Wessex united the kingdoms in the ninth century and defeated the invading Vikings who gave up and dispersed in the summer of 896 AD. After his death in 899, Alfred's son Edward, and his grandsons Æthelstan, Edmund I and Eadred, continued the policy of resistance against the Vikings. Edward's son, Æthelstan, annexed Northumbria, and forced the kings of Wales to submit; then, at the battle of Brunanburh in 937, he defeated an alliance of the Scots, Danes and Vikings to become King of all England.

In 973 Alfred's great-grandson, Edgar, was crowned King of England and Emperor of Britain at Bath. King Edgar only survived for 2 years and Æthelred II was crowned, and although he reigned for thirty eight years, one of the longest reigns in English history, he earned the name "Æthelred the Unready", as he proved to be one of England's most disastrous kings and was succeeded by the Viking Canute who could not control the tide coming in!

When King Canute died in 1035 another dispute arose over the succession which led to intermarriage between Viking and Saxon (mainly Godwin) nobility. Edward the Congessor eventually became King as Canute's step-son and he offered the succession to William of Normandy, himself the son of Viking/Saxon parents. Harold Godwinson's claim to the throne was fairly dubious and having fought off one of Canute's descendants at Stamford Bridge (not the Chelsea FC ground) he was defeated at Hastings by William. There were later wars of succession and it would seem to me to be equally sensible to talk about the history of England from 1485 or 1603 or 1688.

The whole point of this history lesson is to point out that the History of Israel does not begin with Moses but with Abraham. Abraham was not saved because he kept the Law - it wasn't given until centuries after he died. He believed God and it was credited to him as righteousness Galatians 3:6. Those who believe are children of Abraham v7.

This is a stupendous statement! The Jews believed that they were children of Abraham by descent, but Paul is saying it is nothing to do with who your parents were - it is through believing God. Worse than this (as far as the Jews were concerned) The Scripture foresaw that God would justify the Gentiles by faith! v8. The Gentiles! Gentile dogs! Yes, Gentiles! "All nations will be blessed through you." v8 and Genesis 18:18.

How was the thief on the cross saved - by keeping the law? Because he believed.How was Cornelius saved - by his good works? Because he believed.Was your salvation because you kept the law? or because you gave to charity? or because of your good behavior?

How would you ever know you were good enough? Have you been through Numbers and Leviticus and kept every law? Have you always honored your parents? Since your last confession have you erred? Supposing you died in between confessions? Think of the last time you cursed a bad driver. Supposing it led to your fatal car crash. Would you go to hell for the sake of a moment's indiscretion?

But have you believed God when he said that anyone who believed in his son should not perish but have everlasting life? You were saved by believing in Jesus and that life would not be everlasting if it could be forfeited by a moment's bad temper or a wrong hand signal. Or even by playing ball on a Sunday.

There is a craze for DIY. We like to watch a TV program called Homes under the Hammer. Three derelict houses go to auction and the purchasers recondition them. It is wonderful to see Victorian terraced houses restored to better than their former glory. We know the ritual - new central heating, PVC windows, new kitchen, new bathroom, knock down the dividing wall between kitchen and dining room, redecorate throughout in neutral colors. Generally the new owners are builders or get the builders in. Sometimes they decide to do it themselves. Sometimes the job is botched by the DIY attempt. As far as our salvation is concerned, attempting DIY is always going to be a botched job.

But trusting in the Law is worse than that for verse 10 tells us that all who rely on observing the law are under a curse. "Cursed is anyone who does not uphold the words of this law by carrying them out.” Deuteronomy 26:27 Paul is quoting the Judaizers' words back at them and is subtly completing them: "Cursed is everyone who does not continue to do everything written in the Book of the Law" It's not good enough to obey the law in general, Paul is saying that every 't' must be crossed and every 'i' dotted. And no-one is that good at it. He goes on to quote from the prophet Habakkuk (2:4) “the righteous will live by faith.” So, he surmises, clearly no one who relies on the law is justified before God, because the law is not based on faith; on the contrary, it says, “The person who does these things will live by them.”

But Christ redeemed us from the curse of the law by becoming a curse for us, for it is written: “Cursed is everyone who is hung on a tree.” (Deuteronomy 21:33)

Here is substitutionary atonement. We were cursed by the Law because we couldn't keep it. Christ could. He swapped his righteousness for our curse. Can you credit it? No wonder people find it so hard to believe. Why should anyone go through that for me. I heard a story today about the floods in Brisbane. Among those who lost their lives was a 13 year old boy. He insisted that the rescuers save his 10 year old brother first, but when they returned for him, he had been swept away. You might perhaps risk your life for a brother, but for someone who didn't know you, someone to whom you owed no obligation, someone who had even cursed you?

You would only do that if you loved them. And if you loved them like that you'd want to hold on to them, you'd do what you could to make them perfect. He redeemed us in order that the blessing given to Abraham might come to the Gentiles through Christ Jesus, so that by faith we might receive the promise of the Spirit.

I can see some of you saying that we have no problem with the atonement. Of course salvation is all of grace and none of works, but we are talking about sanctification and for that you have to work at obeying the rules.

Beloved, can't you see that it is all one. "So that by faith we might receive the promise of the Spirit." Everyone who is saved receives the Holy Spirit and sanctification is the job of the Spirit, not us. It is his work not ours. Our work is to believe and in some miraculous way this itself is a gift, lest any man should boast.

Sanctification hurts sometimes. We are refined as if by fire, but the Spirit gives us grace to bear it.

I will write more about keeping the Law, but for now lets rejoice in the wonderful gift of grace that rescues us from the curse of the Law.

Saturday, January 08, 2011

I have been asked about why blood transfusions do not make you feel better immediately. The answer lies in the Rapoport-Luebering Shuttle. For those who would like to read the long-winded textbook explanation try this link but for others, here is an explanation.

The main purpose of red cells is to take oxygen from the lungs and deliver it to the tissues. For this purpose they contain hemoglobin. Hemoglobin has a high affinity for oxygen, but at some stage it has to let go of its oxygen so that it can be taken up by the tissues. How it does this is complicated but it is very dependent on the acidity of the tissues, but also on the concentration of a molecule called 2,3-DPG.

The change in oxygen affinity with acidity is known as the Bohr effect. Because the tissues are relatively rich in carbon dioxide and the red cell enzyme carbonic anhydrase readily converts carbon dioxide to carbonic acid, the acidity is greater there than in arterial blood; therefore, the Bohr effect helps the transfer of oxygen to tissues.

The other important factor affecting the oxygen affinity of hemoglobin is the concentration of 2,3-DPG. This molecule can insert into the pocket between β globin subunits in the 4-chain hemoglobin molecule and reduces oxygen affinity by displacing oxygen.

2,3-DPG is synthesized from intermediate molecules on the metabolism of glucose by means of a pathway known as the Rapoport-Luebering shuttle. The means by which glucose is broken down to produce energy for the red cell is known as the Embden Meyerhof pathway which is pictured at the beginning of this article. This second drawing is a blow up of the important area. Normally 1,3-DPG is turned into 3-PG by PG kinase (there is a rare type of hereditary anemia that lacks this enzyme) and this generates energy in the form of ATP. The Rapoport-Luebering shuttle is an alternative by-pass that generates more 2,3-DPG. Just how much glycolysis takes place by the main highway and how much takes the by-pass is a complex issue. It depends on the rate of production of its precursor 1,3-DPG, the level of acidity in the cell, how much ATP there is relative to ADP, the ratio of NAD to NADH, and the concentration of inorganic phosphorus.

The most important function of 2,3-DPG is its effect on the oxygen affinity of hemoglobin. In the deoxygenated state, each hemoglobin molecule can bind one molecule of 2,3-DPG, a reaction leading to reduced oxygen affinity and improved oxygen delivery to tissues. The increased oxygen affinity of stored blood is accounted for by reduced levels of 2,3-DPG. Transfusion of such blood results in an increase in oxygen affinity of circulating blood so that less oxygen is delivered to the tissues. It starts to return toward normal in 7 to 12 hours as the function of the pathway breaking down glucose is restored. A noticeable clinical impairment in oxygen delivery due to low 2,3-DPG levels remains disputed in some quarters, but it would be expected to have its greatest impact when large transfusions are required in critically ill individuals.

First I have a confession. I very seldom censor comments to this blog, but yesterday I had a comment that promoted an alternative therapy for CLL. I did not think it was appropriate to give it the oxygen of publicity on this site, because I think that such alternative therapies, which often involve odd diets and dental clearance and strange supplements, don't do anything for CLL.

CLL is an infinitely variable disease in which spontaneous remissions occur. Patients with the mutated sub-type of CLL, in particular, find that their disease is to some degree subject to homeostatic control. This means that the things that influence normal B cells continue to have an effect on the CLL population. The best example is exercise. One of my patients is able to control his white cell count by running. He has produced impressive graphs which show that when he runs (and he runs enormous distances) his white count falls. But when it comes to the more aggressive subtypes, exercise does little or nothing to control the disease.

Exaggerated claims for lifestyle changes are made, and there is no doubt that most people eat too much, smoke too much and take too little exercise, but there is precious little evidence that changing your lifestyle will do much for your cancer. Anybody who smokes should certainly stop. Second cancers are probably more likely in CLL and it's foolhardy to court one of these by inhaling carcinogens. The evidence that diet influences cancer is much less than certain cancer charities will tell you. Food preserved with nitrites excepted, most dietary associations with cancer have not stood up to rigorous testing. This doesn't mean that I don't advocate healthy eating and regular exercise. Most people will feel better if they follow sensible dietary advice and take plenty of exercise and they will lower their blood pressure, have a trimmer figure and ward off heart disease and stroke.

What about dietary supplements? A normal diet contains everything that humans need to keep healthy. Megadoses of vitamins have been promoted by various individuals including a double Nobel Prize winner in Linus Pauling. The truth is that in most cases the excess vitamins are passed out in the urine. They are safe, but an expensive waste. The exceptions are fat-soluble vitamins A and D. When I was younger there was some laboratory evidence that these vitamins had a physiological effect on cells. The leukemic cell line, HL60, could be made to mature into neutrophils with vitamin A and into monocytes with vitamin D. Indeed, vitamin A derivatives have entered conventional medicine as treatments for acne and promyelocytic leukemia. However these derivatives can be very toxic when taken in excess and are even teratogenic and should not be taken during pregnancy.

Vitamin D is being used for the bone thinning that occurs after the menopause, because its primary action is to control calcium metabolism. Whether it has a role in cancer and in CLL in particular is controversial. Certainly, CLL patients with low levels of D3 have a poorer prognosis, but it is not clear whether this is cause or effect. Clinical trials of vitamin D3 supplements will give us an answer, but until then, those who have faith in D3 should monitor their serum calcium levels, since hypercalcemia can be lethal.

When I talk about a normal diet I mean one that includes meat and vegetables. People who don't eat meat either do so for religious reasons or from distaste at the idea of slaughtering animals or because they have fallen for the propaganda of the vegetarian industry. Strict Hindus are vegans. In rural India such people are likely to be iron deficient since iron from vegetables is poorly absorbed and is not well used for making blood cells. They do not become vitamin B12 deficient because their food is contaminated with bacteria which manufacture the vitamin. In the Western world vegans become vitamin B12 deficient eventually, though B12 stores can last for 20 years if the decision to become a vegan takes place after years on a normal diet. Iron deficiency is not so common because so many foods contain iron supplements. It is most likely to occur in teenage girls.

Some Christians, especially those of the green persuasion, become vegetarians. I'm not sure how they support this theologically, but to my mind the Bible is quite clear on the subject. In Genesis 9:3 God instructs Noah after the Flood: "Everything that lives and moves about will be food for you. Just as I gave you the green plants, I now give you everything." and in the New Testament St Peter's vision in Acts 10:11-15 not only abolishes any food laws, but seems to give the green light to bush tucker: "He saw heaven opened and something like a large sheet being let down to earth by its four corners. It contained all kinds of four-footed animals, as well as reptiles and birds. Then a voice told him, “Get up, Peter. Kill and eat.” “Surely not, Lord!” Peter replied. “I have never eaten anything impure or unclean.” The voice spoke to him a second time, “Do not call anything impure that God has made clean.”

How about herbal medicine? It is certainly true that many of our current drugs including aspirin, quinine, digoxin, atropine and vincristine are derived from plants. One of my old bosses had atrial fibrillation caused by thyrotoxicosis. When he played squash his heart would race, but he kept in the pocket of his shorts some dried foxglove leaves of which he would take a handful for the digitalis effect. That is the problem with herbs. They contain the active ingredient at variable concentrations and often antagonists to the active ingredient as well. Dosing is unpredictable. Better to extract the activity and purify it, then give the optimum dose which has been determined by a clinical trial. There may well be some way of using these active ingredients from herbs like curcumin and green tea, but the raw stuff is variable, weak and unpredictable in its effect.

The placebo effect plays a big part in the beneficial effect of alternative therapies. Practitioners are expert in utilizing it. Spending time with a patient with a good bedside manner and using a spectacular apparatus has an immense placebo effect. How does this work? My daughter thinks it is about neuro-immunology and there is some evidence for this. Pavlov's famous experiment of getting dogs to salivate at the sound of a horn, even when it is not rewarded by food, has been repeated for vaccine studies, so that an immune response can be generated at the sound of a horn, even when no vaccine is given. It is certainly possible that feeling good and optimistic about the future may influence the internal environment of growth factors, chemokines, cytokines, receptors and antibodies.

So I would not discourage people from seeking aromatherapy, exercise, green tea, acupuncture, massage or any other complementary treatment with this proviso: do not let it deter you from an established treatment when the time comes, and do not proselytize so vehemently that you send others on a guilt trip because they are not following your advice.

Friday, January 07, 2011

One of the problems facing doctors treating patients with CLL and, indeed, their patients, is the risk of over-treatment. We have all heard the the surgeon's excuse, "The operation was successful but, unfortunately, the patient died." There is no point in achieving a complete remission is the treatment is so toxic that it kills the patient.

We have all heard about the notorious CALGB study where FCR was followed by Alemtuzumab that had 5 deaths due to infection (cunningly disguised as Grade 5 toxicities). I have heard that there was a 6th death caused by transfusion associated graft versus host disease from receiving a non-irradiated blood transfusion. It is axiomatic that if anyone who has previously received either fludarabine of Alemtuzumab requires a blood or platelet transfusion, they must receive irradiated blood. This was a story of over-treatment.

But it is not what I want to draw attention to today. I want to highlight the risk of the combination of alkylating agent and purine analog use together. The first bit of evidence comes from an old trial - the first CALGB fludarabine trial in fact, (Fludarabine Compared with Chlorambucil as Primary Therapy for Chronic Lymphocytic Leukemia Kanti Rai, BL Peterson, Fred Appelbaum et al N Engl J Med 2000; 343:1750-1757). This compared fludarabine with chlorambucil with the combination of fludarabine and chlorambucil. This third arm was abandoned half way through the trial because it was too toxic but we have the results of long term follow-up. Among 188 patients treated with fludarabine alone there was one case of treatment-related MDS or AML; among 140 treated with chlorambucil alone, there were none; but among 141 patients treated with the combination of these drugs there were 5. The numbers are small and perhaps were due to bad luck, but there is more evidence.

At ASH, Kanti Rai presented the long term follow-up of the CALGB comparison of F with FC (E2997) (Smith MR, Neuberg D, Flinn IW, et al. Increased incidence of therapy related myeloid neoplasia (t-MN) after initial therapy for CLL with fludarabine-cyclophosphamide (FC) vs fludarabine (F): long-term follow-up of US Intergroup Study E2997. Program and abstracts of the 52nd American Society of Hematology Annual Meeting and Exposition; December 4-7, 2010; Orlando, Florida. Abstract 924.) Among 137 patients who had fludarabine alone, there were 4 cases of treatment related MDS or AML but among 141 who received FC there were 9 cases. Interestingly, among those who had had the IGVH mutational status done, all 7 were mutated (ie low risk).

We have two papers reporting on the long term follow up of FCR. Tam et al (Tam CS, O’Brien S, Wierda W, et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008;112:975-980.) found 8 cases out of 300 developing MDS or AML, while Carney and Mulligan (Carney DA, Mulligan SP. Chronic lymphocytic leukaemia: current first-line therapy. Intern Med J. 2009;39:44-48) found 3 cases out of 61.

What this says is that there is a small but definite risk of treatment related MDS/AML from a purine analog/alkylating agent combination. This does not impact on overall survival, but it is probably an unnecessary risk in some patients. Since there seems to be a greater danger in the mutated subset - possibly because they live longer and have more time for the MDS to mature. It pushes me into saying that those with mutated IGHV genes might be better served by using chlorambucil and rituximab as first line treatment.

My theory of why the combination is so much more risky is that alkylating agents do cause genetic damage which is normally dealt with by immune surveillance but since immune surveillance is severely curtailed by fludarabine, the aberrant clones are permitted to expand and become lethal.

Wednesday, January 05, 2011

I have had a bit of a setback. On Monday my Hickman line was flushed as usual without incident, but around 4 hours later I began to feel unwell. I had a headache, I thought I was going to have a rigor although it came to nothing, my limbs began to ache and I became flushed. My temperature had gone up to 99.6 and I called the hospital.

Both they and I thought a line infection was a possibility though I had a flu jab a few days ago, and I was certainly incubating a cold. Obviously I needed to have blood cultures taken, but they decided that it would be sensible to keep me in over night in case this was a Gram negative line infection.

I spent a very uncomfortable night in hospital. At first my temperature rose to 99.8 with a pulse rate of 114. My BP was normal and I was sneezing and coughing. I only slept for about three hours and by the next morning I was quite cross from lack of sleep, in part due to my cold, but in part due to the ward noises and the fact that a light above my bed and been on all night.

My temperature had settled to 98.4 the next morning and my pulse to 90. I felt better in myself and was anxious to go home.

Today, I had to go in again for my pre-chemo assessment before the next dose on Saturday. The Registrar greeted me with the news that a gram negative bacterium had been grown from my blood culture and that the line would have to come out. Rather than wait a couple of hours to have it removed, I went home for lunch and when I returned the decision had been changed. I was to be started on a course of antibiotics and they would review the decision when the bug and its antibiotic sensitivities had been identified. So I am up in the air at the moment band not sure where I will fall.

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Born in Worcester, England 1943; school at Farnborough, Hampshire 1954-62; University 1962-7 and junior doctor posts 1967-74 in Bristol; Consultant Haematologist Bournemouth 1974-2003; Professor of Immunohaematology Southampton 1986 to present. Honorary Consultant Haematologist Kings College Hospital, London, 2004-present. After 5 years of working part time researching, writing, reviewing, editing, speaking, sitting on committees, advising, answering questions and thinking, I now think of myself as fully retired apart from my role as Editor in Chief of the medical journal Leukemia Research. I was awarded the Binet-Rai medal for outstanding research in CLL in 2002 and this has been my most sucessful area of research, but I have also made important contributions in the fields of apheresis, stem cell transplantation, myeloma, myelodysplastic syndrome, antibody therapy, cytokine therapy and DNA vaccines. I was once mascot for Aldershot Town Football. Club. Married to Diane for 44 years. Four children, Karen, Richard, Angela and David.